Abstract
The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the "hybridization" of a variety of KAc-binding fragments with a tetrahydroquinoline scaffold that makes optimal interactions with the LPF shelf, imparting enhanced potency and selectivity to the hybridized ligand. To demonstrate the utility of our hybridization approach, two analogues containing unique Asn binders and the optimized tetrahydroquinoline moiety were rapidly optimized to yield single-digit nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1) and the broader bromodomain family.
Publication types
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Asparagine / chemistry
-
Asparagine / metabolism
-
Binding Sites
-
Cell Cycle Proteins
-
Crystallography, X-Ray
-
Female
-
Fluorescence Resonance Energy Transfer / methods
-
High-Throughput Screening Assays / methods*
-
Mice, Inbred Strains
-
Molecular Docking Simulation
-
Nuclear Proteins / antagonists & inhibitors
-
Protein Domains
-
Pyrazoles / chemistry
-
Pyridines / chemistry
-
Quinolines / chemistry
-
Transcription Factors / antagonists & inhibitors
-
p300-CBP Transcription Factors / antagonists & inhibitors*
-
p300-CBP Transcription Factors / chemistry
-
p300-CBP Transcription Factors / metabolism
Substances
-
BRD4 protein, human
-
Cell Cycle Proteins
-
GNE-781
-
Nuclear Proteins
-
Pyrazoles
-
Pyridines
-
Quinolines
-
Transcription Factors
-
Asparagine
-
1,2,3,4-tetrahydroquinoline
-
p300-CBP Transcription Factors